Requirement of c-Myb for p210BCR/ABL-dependent transformation of hematopoietic progenitors and leukemogenesis

Department of Cancer Biology, and Kimmel Cancer Center, Thomas Jefferson University Medical College, Philadelphia, PA 19107, USA.
Blood (Impact Factor: 10.45). 06/2008; 111(9):4771-9. DOI: 10.1182/blood-2007-08-105072
Source: PubMed


The c-Myb gene encodes a transcription factor required for proliferation and survival of normal myeloid progenitors and leukemic blast cells. Targeting of c-Myb by antisense oligodeoxynucleotides has suggested that myeloid leukemia blasts (including chronic myelogenous leukemia [CML]-blast crisis cells) rely on c-Myb expression more than normal progenitors, but a genetic approach to assess the requirement of c-Myb by p210(BCR/ABL)-transformed hematopoietic progenitors has not been taken. We show here that loss of a c-Myb allele had modest effects (20%-28% decrease) on colony formation of nontransduced progenitors, while the effect on p210(BCR/ABL)-expressing Lin(-) Sca-1(+) and Lin(-) Sca-1(+)Kit(+) cells was more pronounced (50%-80% decrease). Using a model of CML-blast crisis, mice (n = 14) injected with p210(BCR/ABL)-transduced p53(-/-)c-Myb(w/w) marrow cells developed leukemia rapidly and had a median survival of 26 days, while only 67% of mice (n = 12) injected with p210(BCR/ABL)-transduced p53(-/-)c-Myb(w/d) marrow cells died of leukemia with a median survival of 96 days. p210(BCR/ABL)-transduced c-Myb(w/w) and c-Myb(w/d) marrow progenitors expressed similar levels of the c-Myb-regulated genes c-Myc and cyclin B1, while those of Bcl-2 were reduced. However, ectopic Bcl-2 expression did not enhance colony formation of p210(BCR/ABL)-transduced c-Myb(w/d) Lin(-)Sca-1(+)Kit(+) cells. Together, these studies support the requirement of c-Myb for p210(BCR/ABL)-dependent leukemogenesis.

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    • "Using TRANSFAC analysis we have identified several transcription factor binding sites, including MYB, STAT5A, IKZF1, MZF1, SP1 and LMO2, in the miR-150 putative promoter region. MYB and STAT5A expression are enhanced by BCR-ABL expression and both are essential for BCR-ABL mediated transformation [58,59]. LMO2 is important in murine hematopoiesis and the inverse relationship between miR-150 and LMO2 expression in published reports suggests LMO2 may repress miR-150 expression in B and T cell and erythroid/megakaryocytic differentiation [32,60,61]. "
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    ABSTRACT: In acute myeloid leukemia (AML) and blast crisis (BC) chronic myeloid leukemia (CML) normal differentiation is impaired. Differentiation of immature stem/progenitor cells is critical for normal blood cell function. MicroRNAs (miRNAs or miRs) are small non-coding RNAs that interfere with gene expression by degrading messenger RNAs (mRNAs) or blocking protein translation. Aberrant miRNA expression is a feature of leukemia and miRNAs also play a significant role in normal hematopoiesis and differentiation. We have identified miRNAs differentially expressed in AML and BC CML and identified a new role for miR-150 in myeloid differentiation. Expression of miR-150 is low or absent in BC CML and AML patient samples and cell lines. We have found that expression of miR-150 in AML cell lines, CD34+ progenitor cells from healthy individuals, and primary BC CML and AML patient samples at levels similar to miR-150 expression in normal bone marrow promotes myeloid differentiation of these cells. MYB is a direct target of miR-150, and we have identified that the observed phenotype is partially mediated by MYB. In AML cell lines, differentiation of miR-150 expressing cells occurs independently of retinoic acid receptor α (RARA) signaling. High-throughput gene expression profiling (GEP) studies of the AML cell lines HL60, PL21, and THP-1 suggest that activation of CEPBA, CEBPE, and cytokines associated with myeloid differentiation in miR-150 expressing cells as compared to control cells contributes to myeloid differentiation. These data suggest that miR-150 promotes myeloid differentiation, a previously uncharacterized role for this miRNA, and that absent or low miR-150 expression contributes to blocked myeloid differentiation in acute leukemia cells.
    PLoS ONE 09/2013; 8(9):e75815. DOI:10.1371/journal.pone.0075815 · 3.23 Impact Factor
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    • "Interestingly, two of them (Sp1 and CEBPa) are mainly involved in the regulation of gene expression but, more importantly, the other two (c-myb and MZF-1) are typically linked to the hematopoietic system. In fact, c-myb is required for regulating the proliferation and survival of normal myeloid progenitors and leukemic blast cells, while MZF-1 is usually associated with the differentiation of the hematopoietic stem cells (Lidonnici et al., 2008; Morris et al., 1995). Our chromatin immunoprecipitation experiments showed that the four selected transcription factors were only partially recruited to PLC-b1 promoter before the start of epigenetic therapy. "
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    ABSTRACT: The roles of phosphoinositide-specific phospholipase C (PLC) have been extensively investigated in diverse cell lines and pathological conditions. Among the PLC isozmes, primary PLCs, PLC-β and PLC-γ, are directly activated by receptor activation, unlike other secondary PLCs (PLC-ɛ, PLC-δ1, and PLC-η1). PLC-β isozymes are activated by G protein couple receptor and PLC-γ isozymes are activated by receptor tyrosine kinase (RTK). Primary PLCs are differentially expressed in different tissues, suggesting their specific roles in diverse tissues and regulate a variety of physiological and pathophysiological functions. Thus, dysregulation of phospholipases contributes to a number of human diseases and primary PLCs have been identified as therapeutic targets for prevention and treatment of diseases. Here we review the roles of primary PLCs in physiology and their impact in pathology.
    08/2013; 53(3). DOI:10.1016/j.jbior.2013.08.003
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    • "In particular, MDS patients responding to azacitidine therapy were reported to show a specific recruitment to PI- PLCb1 promoter of myeloid zinc finger (MZF)-1, but not c-myb. This is particularly appealing, since MZF-1 plays a role in myeloid differentiation (Morris et al., 1995), whereas c-myb is specifically associated with hematopoietic stem cell proliferation (Lidonnici et al., 2008), therefore confirming the involvement of PI-PLCb1 in azacitidine-induced myeloid differentiation (Fig. 1). "
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    ABSTRACT: Myelodysplastic syndromes (MDS), clonal hematopoietic stem-cell disorders mainly affecting older adult patients, show ineffective hematopoiesis in one or more of the lineages of the bone marrow. Most MDS are characterized by anemia, and a number of cases progresses to acute myeloid leukemia (AML). Indeed, the molecular mechanisms underlying the MDS evolution to AML are still unclear, even though the nuclear signaling elicited by PI-PLCβ1 has been demonstrated to play an important role in the control of the balance between cell cycle progression and apoptosis in MDS cells. Here we review both the role of epigenetic therapy on PI-PLCβ1 promoter and the changes in PI-PLCβ1 expression in MDS patients treated for anemia.
    09/2012; 53(1). DOI:10.1016/j.jbior.2012.09.009
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